The goal of Research Project by Veazey (Nonhuman primate studies to develop an RNAi microbicide) is to evaluate[unreadable] the efficacy, safety, potency, and duration of effect of RNA interference (RNAi) technology in preventing[unreadable] vaginal transmission of HIV-1, using the simian/human immunodeficiency virus (SHIV) vaginal transmission[unreadable] model in rhesus macaques. The Leader will be Ronald Veazey, DVM, PhD, and the project will be located at[unreadable] the Tulane National Primate Research Center, Tulane, LA. For these studies, we will receive CCR5 specific[unreadable] RNAi from the Research Support Core which we will use in determining the depth or penetration, level of[unreadable] CCR5 downregulation, safety, and efficacy in preventing vaginal transmission of the CCR5 tropic[unreadable] SHIV162P3 virus to macaques when used as a microbicide. This project will coordinate closely with the[unreadable] leaders of the other research projects involved in testing these drugs in human explant and murine model[unreadable] systems (Research Projects by Lieberman and Palliser, and Research Support Cores). We will examine the safety and efficacy[unreadable] of the RNAi after topical application to the macaque vagina, by performing colposcopy and vaginal biopsy[unreadable] after vaginal administrations of the drugs to carefully rule out local inflammatory responses and to monitor[unreadable] levels of CCR5 expression in various tissues. CCR5 specific RNAi will also be assessed for its efficacy in[unreadable] downregulating CCR5 expression in vaginal and other tissues, as well as its efficacy and duration of effects[unreadable] in preventing vaginal SHIV transmission to macaques. The specific aims of research project by Veazey are to:[unreadable] Specific Aim 1. Determine whether siRNAs are efficiently taken up by vaginal and cervical tissues in the[unreadable] macaque and whether vaginal application of siRNAs silences macaque CCR5 expression in vivo;[unreadable] Specific Aim 2. Determine whether first generation, unmodified CCR5 siRNAs given before and after[unreadable] challenge with SHIV 162P3 protect against vaginal transmission;[unreadable] Specific Aim 3. Evaluate dose response to determine the amount of unmodified siRNA required to protect[unreadable] against challenge, and whether increasing amounts of siRNA cause vaginal irritation, inflammation,[unreadable] interferon induction or other unanticipated toxicity, and;[unreadable] Specific Aim 4. Determine whether optimized siRNAs against CCR5 and viral sequences alone and in[unreadable] combination provide superior protection than unmodified CCR5 siRNAs alone.